Skip to main content

Advertisement

SpringerLink
Log in

Low-dose fractionated radiotherapy and concomitant chemotherapy for recurrent or progressive glioblastoma

Final report of a pilot study

Niedrigdosierte fraktionierte Strahlentherapie und gleichzeitige Chemotherapie bei rezidiviertem oder progredientem Glioblastom

Abschlussbericht einer Pilotstudie

  • Original article
  • Published:
Strahlentherapie und Onkologie Aims and scope Submit manuscript

Abstract

Backgroud

Evaluated in this study were the feasibility and the efficacy of concurrent low dose fractionated radiotherapy (LD-FRT) and chemotherapy as palliative treatment for recurrent/progressive glioblastoma multiforme (GBM).

Patients and methods

Eligible patients had recurrent or progressive GBM, Karnofsky performance status ≥ 70, prior surgery, and standard radiochemotherapy treatment. Recurrence/progression disease during temozolomide (TMZ) received cisplatin (CDDP; 30 mg/m2 on days 1, 8, 15), fotemustine (FTM; 40 mg/m2 on days 2, 9, 16), and concurrent LD-FRT (0.3 Gy twice daily); recurrence/progression after 4 months from the end of adjuvant TMZ were treated by TMZ (150/200 mg/m2 on days 1–5) concomitant with LD-FRT (0.4 Gy twice daily). Primary endpoints were safety and toxicity.

Results

A total of 32 patients were enrolled. Hematologic toxicity G1–2 was observed in 18.7 % of patients and G3–4 in 9.4 %. One patient (3.1 %) had complete response, 3 (9.4 %) had partial response, 8 (25 %) had stable disease for at least 8 weeks, while 20 patients (62.5 %) experienced progressive disease. The clinical benefit was 37.5 %. Median progression-free survival (PFS) and overall survival (OS) were 5 and 8 months, respectively. Survival rate at 12 months was of 27.8 %.

Conclusion

LD-FRT and chemotherapy for recurrent/progressive GBM have a good toxicity profile and clinical outcomes, even though further investigation of this novel palliative treatment approach is warranted.

Zusammenfassung

Hintergrund

Bewertung der Möglichkeit und Wirksamkeit einer gleichzeitigen niedrigdosierten und fraktionierten Strahlentherapie mit Chemotherapie als palliative Behandlung bei rezidivierendem/progressivem Glioblastoma multiforme.

Patienten und Methoden

Patienten mit einem Glioblastoma multiforme im Rezidiv oder in Progression nach vorhergehender Operation und Standard-Radiochemotherapie und einem Karnofsky-Performance-Status > 70 konnten in die Studie eingeschlossen werden. Die Patienten, die ein Rezidiv/Progression der Krankheit während Temozolomid-Behandlung erlitten hatten, erhielten Cisplatin (30 mg/m2 an den Tagen 1, 8, 15), Fotemustin (40 mg/m2 an den Tagen 2, 9, 16) und gleichzeitig eine niedrigdosierte Strahlentherapie (0,3 Gy bid). Patienten mit Rezidiv/Progression mehr als 4 Monaten nach Ende der adjuvanten Temozolomid-Behandlung wurden mit Temozolomid (150/200 mg/m2 an den Tagen 1–5) und gleichzeitig mit niedrigdosierter Strahlentherapie (0,4 Gy bid) behandelt. Primäre Endpunkte waren Sicherheit und Toxizität.

Ergebnisse

Es wurden 32 Patienten eingeschlossen. Hämatologische Toxizität vom Grad 1–2 wurde in 18,7 % der Patienten beobachtet, und vom Grad 3–4 in 9,4 %. Ein Patient (3,1 %) hatte eine komplette Remission, 3 Patienten (9,4 %) eine partielle Remission und 8 (25 %) eine Stabilisierung der Erkrankung für mindestens 8 Wochen. Bei 20 Patienten (62,5 %) schritt die Erkrankung weiter fort. Einen klinischen Nutzen hatten 37,5 % der Patienten. Die mediane progressionsfreie Überlebenszeit und die Gesamtüberlebenszeit betrugen 5 und 8 Monate. Die Überlebensrate nach 12 Monaten lag bei 27,8 %.

Schlussfolgerung

Die niedrigdosierte fraktionierte Strahlentherapie mit gleichzeitiger Chemotherapie hat ein gutes Nebenwirkungsprofil und zeigt gute klinischen Ergebnisse bei rezidivierenden/progressiven Glioblastomen, wenn auch weitere Untersuchungen zu diesem neuartigen Ansatz der palliativen Behandlung notwendig sind.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

References

  1. Guckenberger M, Mayer M, Buttmann M et al (2011) Prolonged survival when temozolomide is added to accelerated radiotherapy for glioblastoma multiforme. Strahlenther Onkol 187(9):548–554

    Article  PubMed  Google Scholar 

  2. Lang O, Liebermeister E, Liesegang J, Sautter-Bihl ML (1998) Radiotherapy of glioblastoma multiforme. Feasibility of increased fraction size and shortened overall treatment. Strahlenther Onkol 174(12):629–632

    Article  CAS  PubMed  Google Scholar 

  3. American Cancer Society (2008) Cancer facts & figures 2008. American Cancer Society, Atlanta

  4. Stupp R, Mason WP, Bent MJ van den et al (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996

    Article  CAS  PubMed  Google Scholar 

  5. Jansen EP, Dewit LG, Herk M van, Bartelink H (2000) Target volumes in radiotherapy for high-grade malignant glioma of the brain. Radiother Oncol 56(2):151–156

    Article  CAS  PubMed  Google Scholar 

  6. Wallner KE, Galicich JH, Krol G et al (1989) Patterns of failure following treatment for glioblastoma multiforme and anaplastic astrocytoma. Int J Radiat Oncol Biol Phys 16(6):1405–1409

    Article  CAS  PubMed  Google Scholar 

  7. Chamberlain MC, Kormanik PA (1998) Practical guidelines for the treatment of malignant gliomas. West J Med 168(2):114–120

    CAS  PubMed Central  PubMed  Google Scholar 

  8. Vredenburgh JJ, Desjardins A, Herndon JE 2nd et al (2007) Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol 25(30):4722–4729

    Article  CAS  PubMed  Google Scholar 

  9. Tselis N, Kolotas C, Birn G et al (2007) CT-guided interstitial HDR brachytherapy for recurrent glioblastoma multiforme. Long-term results. Strahlenther Onkol 183(10):563–570

    Article  PubMed  Google Scholar 

  10. Henke G, Paulsen F, Steinbach JP et al (2009) Hypofractionated reirradiation for recurrent malignant glioma. Strahlenther Onkol 185(2):113–119

    Article  PubMed  Google Scholar 

  11. Fokas E, Wacker U, Gross MW (2009) Hypofractionated stereotactic reirradiation of recurrent glioblastomas: a beneficial treatment option after high-dose radiotherapy? Strahlenther Onkol 185(4):235–240

    Article  PubMed  Google Scholar 

  12. Wong ET, Hess KR, Gleason MJ et al (1999) Outcomes and prognostic factors in recurrent glioma patients enrolled onto phase II clinical trial. J Clin Oncol 17:2572–2578

    CAS  PubMed  Google Scholar 

  13. Galanis E, Buckner JC, Maurer MJ et al (2005) Phase II trial of temsirolimus (CC1-779) in recurrent glioblastoma multiforme: a North Central Cancer Treatment Group study. J Clin Oncol 23:5294–5304

    Article  CAS  PubMed  Google Scholar 

  14. Niyazi M, Siefert A, Schwarz SB et al (2011) Therapeutic options for recurrent malignant glioma. Radiother Oncol 98(1):1–14

    Article  PubMed  Google Scholar 

  15. Perry JR, Rizek P, Cashman R et al (2008) Temozolomide rechallenge in recurrent malignant glioma by using a continuous temozolomide schedule: the “rescue” approach. Cancer 113(8):2152–2157

    Article  CAS  PubMed  Google Scholar 

  16. Short SC, Mitchell SA, Boulton P et al (1999) The response of human glioma cell lines to low-dose radiation exposure. Int J Radiat Biol 75:1341–1348

    Article  CAS  PubMed  Google Scholar 

  17. Short S, Mayes C, Woodcock M et al (1999) Low-dose hypersensitivity in the T98G human glioblastoma cell line. Int J Radiat Biol 75:847–855

    Article  CAS  PubMed  Google Scholar 

  18. Beauchesne PD, Bertrand S, Branche R et al (2003) Human malignant glioma cell lines are sensitive to low radiation doses. Int J Cancer 105:33–40

    Article  CAS  PubMed  Google Scholar 

  19. Krause M, Wohlfarth J, Georgi B et al (2005) Low-dose hyperradiosensitivity of human glioblastoma cell lines in vitro does not translate into improved outcome of ultrafractionated radiotherapy in vivo. Int J Radiat Biol 81(10):751–758

    Article  CAS  PubMed  Google Scholar 

  20. Chendil D, Oakes R, Alcock RA et al (2000) Low dose fractionated radiation enhances the radiosensitization effect of paclitaxel in colorectal tumor cells with mutant p53. Cancer 89:1893–1900

    Article  CAS  PubMed  Google Scholar 

  21. Short SC, Kelly J, Mayes CR et al (2001) Low-dose hypersensitivity after fractionated low-dose irradiation in vitro. Int J Radiat Biol 77:655–664

    Article  CAS  PubMed  Google Scholar 

  22. Dey S, Spring PM, Arnold S et al (2003) Low-dose fractionated radiation potentiates the effects of paclitaxel in wild-type and mutant p53 head and neck tumor cell lines. Clin Cancer Res 9:1557–1565

    CAS  PubMed  Google Scholar 

  23. Gupta S, Arnold AM, Spring P et al (2004) Low-dose fractionated radiation potentiates the effect of cisplatin independent of the hyper-radiation sensitivity phenomenon in human lung cancer cell lines [Abstract]. Proc Am Assoc Cancer Res 45

  24. Arnold SM, Regine WF, Ahmed MM et al (2004) Low-dose fractionated radiation as a chemopotentiator of neoadjuvant paclitaxel and carboplatin for locally advanced squamous cell carcinoma of the head and neck: results of a new treatment paradigm. Int J Radiat Oncol Biol Phys 58:1411–1417

    Article  CAS  PubMed  Google Scholar 

  25. Spring PM, Arnold SM, Shajahan S et al (2004) Low dose fractionated radiation potentiates the effects of taxotere in nude mice xenografts of squamous cell carcinoma of head and neck. Cell Cycle 3:479–485

    Article  CAS  PubMed  Google Scholar 

  26. Regine WF, Hanna N, Garofalo MC et al (2007) Low-dose radiotherapy as a chemopotentiator of gemcitabine in tumors of the pancreas or small bowel: a phase I study exploring a new treatment paradigm. Int J Radiat Oncol Biol Phys 68(1):172–177

    Article  CAS  PubMed  Google Scholar 

  27. Simpson L, Galanis E (2006) Recurrent glioblastoma multiforme: advances in treatment and promising drug candidates. Expert Rev Anticancer Ther 6(11):1593–1607

    Article  CAS  PubMed  Google Scholar 

  28. Brandes AA, Tosoni A, Basso U et al (2004) Second-line chemotherapy with irinotecan plus carmustine in glioblastoma recurrent or progressive after first-line temozolomide chemotherapy: a phase II study of the Gruppo Italiano Cooperativo di Neuro-Oncologia (GICNO). J Clin Oncol 22(23):4779–4786

    Article  CAS  PubMed  Google Scholar 

  29. Franceschi E, Omuro AM, Lassman AB et al (2005) Salvage temozolomide for prior temozolomide responders. Cancer 104(11):2473–2476

    Article  CAS  PubMed  Google Scholar 

  30. Meulemans A, Giroux B, Hannoun P et al (1991) Comparative diffusion study of two nitrosoureas: carmustine and fotemustine in normal rat brain, human and rat brain biopsies. Chemotherapy 37:86–92

    Article  CAS  PubMed  Google Scholar 

  31. Fischel JL, Formento P, Etienne MC, Gioanni J et al (1990) In vitro chemosensitivity testing of fotemustine (S 10036), a new antitumor nitrosourea. Cancer Chemother Pharmacol 25:337–341

    Article  CAS  PubMed  Google Scholar 

  32. Fabrini MG, Silvano G, Lolli I et al (2009) A multi-institutional phase II study on second-line fotemustine chemotherapy in recurrent glioblastoma. J Neurooncol 92(1):79–86

    Article  CAS  PubMed  Google Scholar 

  33. Scoccianti S, Detti B, Sardaro A et al (2008) Second-line chemotherapy with fotemustine in temozolomide-pretreated patients with relapsing glioblastoma: a single institution experience. Anticancer Drugs 19(6):613–620

    Article  CAS  PubMed  Google Scholar 

  34. De Wit MC, Bruin HG de, Eijkenboom W et al (2004) Immediate post-radiotherapy changes in malignant glioma can mimic tumor progression. Neurology 63(3):535–537

    Article  Google Scholar 

  35. Emami B, Lyman j, Brown A et al (1991) Tolerance of normal tissue to therapeutic irradiation. Int J Radiat Oncol Biol Phys 21:109–122

    Article  CAS  PubMed  Google Scholar 

  36. Lawrence YR, Li XA, Naqa I el et al (2010) Radiation dose–volume effects in the brain. Int J Radiat Oncol Biol Phys 76(3 Suppl):S20–S27

    Article  PubMed Central  PubMed  Google Scholar 

  37. Balducci M, D’Agostino GR, Manfrida S et al (2010) Radiotherapy and concomitant temozolomide during the first and last weeks in high grade gliomas: long-term analysis of a phase II study. J Neurooncol 97(1):95–100

    Article  CAS  PubMed  Google Scholar 

  38. De Bonis P, Anile C, Pompucci A et al (2012) Safety and efficacy of Gliadel wafers for newly diagnosed and recurrent glioblastoma. Acta Neurochir (Wien) 154(8):1371–1378

    Google Scholar 

  39. Rodier JM, Da Costa L, Adams D et al (1996) Fotemustine and cisplatin association in patients with recurrent malignant glioma. Proc Am Sol Clin

  40. Lambin P, Malaise EP, Joiner MC (1994) The effect of very low radiation doses on the human bludder cell line RT112. Radiother Oncol 32:63–72

    Article  CAS  PubMed  Google Scholar 

  41. Common Terminology Criteria for Adverse Events (CTCAE) and Common Toxicity Criteria (CTC) v4.0. ctep.cancer.gov/reporting/ctc.html. Accessed 29. Dec 2013

  42. Macdonald DR, Cascino TL, Schold SC Jr, Cairncross JG (1990) Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol 8(7):1277–1280

    CAS  PubMed  Google Scholar 

  43. CBTRUS Statistical Report: Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2004–2008 (Revised March 23, 2012). http://www.cbtrus.org/reports/reports.html. Accessed 29. Dec 2013

  44. Stupp R, Hegi ME, Mason WP et al (2009) Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 10(5):459–466

    Article  CAS  PubMed  Google Scholar 

  45. Taghian A, Ramsay J, Allalunis-Turner J et al (1993) Intrinsic radiation sensitivity may not be the major determinant of the poor clinical outcome of glioblastoma multiforme. Int J Radiat Oncol Biol Phys 25(2):243–249

    Article  CAS  PubMed  Google Scholar 

  46. Johannessen TC, Bjerkvig R, Tysnes BB (2008) DNA repair and cancer stem-like cells—potential partners in glioma drug resistance? Cancer Treat Rev 34(6):558–567

    Article  CAS  PubMed  Google Scholar 

  47. Lowe SW, Ruley HE, Jacks T, Housman DE et al (1993) P53-dependent apoptosis modulates the cytotoxicity of anticancer agents. Cell 74:957–967

    Article  CAS  PubMed  Google Scholar 

  48. Benjamin B, David C, Dieter L et al (2010) Defective p53 antiangiogenic signaling in glioblastoma. Neuro Oncol 12(9):894–907

    Article  Google Scholar 

  49. Nieder C, Adam M, Molls M, Grosu AL (2006) Therapeutic options for recurrent high-grade glioma in adult patients: recent advances. Crit Rev Oncol Hematol 60(3):181–193

    Article  PubMed  Google Scholar 

  50. Franceschi E, Tosoni A, Bartolini S et al (2009) Treatment options for recurrent glioblastoma: pitfalls and future trends. Expert Rev Anticancer Ther 9(5):613–619

    Article  PubMed  Google Scholar 

  51. Lin SH, Kleinberg LR (2008) Carmustine wafers: localized delivery of chemotherapeutic agents in CNS malignancies. Expert Rev Anticancer Ther 8(3):343–359

    Article  CAS  PubMed  Google Scholar 

  52. Attenello FJ, Mukherjee D, Datoo G et al (2008) Use of Gliadel (BCNU) wafer in the surgical treatment of malignant glioma: a 10-year institutional experience. Ann Surg Oncol 15(10):2887–2893

    Article  PubMed  Google Scholar 

  53. Hart MG, Grant R, Garside R et al (2008) Chemotherapeutic wafers for high grade glioma. Cochrane Database Syst Rev 3:CD007294

    PubMed  Google Scholar 

  54. Gilbert MR (2011) Recurrent glioblastoma: a fresh look at current therapies and emerging novel approaches. Semin Oncol 38(Suppl 4):S21–S33

    Article  PubMed  Google Scholar 

  55. Marples B, Wouters BG, Collis SJ et al (2004) Low-dose hyper-radiosensitivity: a consequence of ineffective cell cycle arrest of radiationdamaged G2-phase cells. Radiat Res 161:247–255

    Article  CAS  PubMed  Google Scholar 

  56. Enns L, Bogen KT, Wizniak J et al (2004) Low- dose radiation hypersensitivity is associated with p53-dependent apoptosis. Mol Cancer Res 2(10):557–566

    CAS  PubMed  Google Scholar 

  57. Brandes AA, Tosoni A, Cavallo G et al (2006) Temozolomide 3 weeks on and 1 week off as first-line therapy for recurrent glioblastoma: phase II study from gruppo italiano cooperativo di neuro-oncologia (GICNO). Br J Cancer 95:1155–1160

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  58. Brada M, Hoang-Xuan K, Rampling R et al (2001) Multicenter phase II trial of temozolomide in patients with glioblastoma multiforme at first relapse. Ann Oncol 12:259–266

    Article  CAS  PubMed  Google Scholar 

  59. Yung WK, Albright RE, Olson J et al (2000) A phase II study of temozolomide vs. procarbazine in patients with Glioblastoma multiforme at first relapse. Br J Cancer 83:588–593

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  60. Wick W, Steinbach JP, Kuker WM et al (2004) One week on/one week off: a novel active regimen of temozolomide for recurrent glioblastoma. Neurology 62:2113–2115

    Article  CAS  PubMed  Google Scholar 

  61. Wick A, Felsberg J, Steinbach JP et al (2007) Efficacy and tolerability of temozolomide in an alternating weekly regimen in patients with recurrent glioma. J Clin Oncol 25:3357–3361

    Article  CAS  PubMed  Google Scholar 

  62. Joiner MC, Denekamp J, Maughan RL (1986) The use of ‘top-up’ experiments to investigate the effect of very small doses per fraction in mouse skin. Int J Radiat Biol Relat Stud Phys Chem Med 49:565–580

    Article  CAS  PubMed  Google Scholar 

  63. Joiner MC, Johns H (1988) Renal damage in the mouse: the response to very small doses per fraction. Radiat Res 114:385–398

    Article  CAS  PubMed  Google Scholar 

  64. Turesson I, Nyman J, Qvarnström F et al (2010) A low-dose hypersensitive keratinocyte loss in response to fractionated radiotherapy is associated with growth arrest and apoptosis. Radiother Oncol 94(1):90–101

    Article  CAS  PubMed  Google Scholar 

  65. Rachidi W, Harfourche G, Lemaitre G et al (2007) Sensing radiosensitivity of human epidermal stem cells. Radiother Oncol 83(3):267–276

    Article  CAS  PubMed  Google Scholar 

  66. Gay H (2010) Role of the linear-quadratic model in high doses per fraction. Radiother Oncol 94(1):122–123

    Article  Google Scholar 

  67. Courdi A (2010) High doses per fraction and the linear-quadratic model. Radiother Oncol 94(1):121–122

    Article  PubMed  Google Scholar 

  68. Short SC, Woodcock M, Marples B, Joiner MC et al (2003) Effects of cell cycle phase on low-dose hyper-radiosensitivity. Int J Radiat Biol 79(2):99–105

    Article  CAS  PubMed  Google Scholar 

  69. Beauchesne P, Bernier V, Carnin C et al (2010) Prolonged survival for patients with newly diagnosed, inoperable glioblastoma with 3-times daily ultrafractionated radiation therapy. Neuro Oncol 12(6):595–602

    Article  PubMed Central  PubMed  Google Scholar 

  70. Valentini V, Massaccesi M, Balducci M et al (2010) Low-dose hyperradiosensitivity: is there a place for future investigation in clinical settings? Int J Radiat Oncol Biol Phys 76:535–539

    Article  PubMed  Google Scholar 

  71. Mantini G, Valentini V, Meduri B et al (2102) Low-dose radiotherapy as a chemo-potentiator of a chemotherapy regimen with pemetrexed for recurrent non-small-cell lung cancer: A prospective phase II study. Radiother Oncol 105:161–166

    Article  Google Scholar 

  72. Balducci M, Chiesa S, Diletto B et al (2012) Low-dose fractionated radiotherapy and concomitant chemotherapy in glioblastoma multiforme with poor prognosis: a feasibility study. Neuro Oncol 14:79–86

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Compliance with ethical guidelines

Conflict of interest. M. Balducci, B. Diletto, S. Chiesa, M.A. Gambacorta, G.R. D’Agostino, M. Ferro, C. Colosimo, G. Maira, C. Anile, and V. Valentini state that there are no conflicts of interest.

The accompanying manuscript does not include studies on humans or animals.

Funding statement

There is no funding supporting the research.

Author information

Authors and Affiliations

  1. Department of Radiation Oncology, Catholic University of the Sacred Heart, Largo Agostino Gemelli, 1, 00168, Rome, Italy

    M. Balducci, B. Diletto, S. Chiesa, G.R. D’Agostino, M.A. Gambacorta, M. Ferro & V. Valentini

  2. Department of Radiology, Catholic University of the Sacred Heart, Rome, Italy

    C. Colosimo

  3. Department of Neurosurgery, Catholic University of the Sacred Heart, Rome, Italy

    G. Maira & C. Anile

Authors
  1. M. Balducci
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. B. Diletto
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S. Chiesa
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. G.R. D’Agostino
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M.A. Gambacorta
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M. Ferro
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. C. Colosimo
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. G. Maira
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. C. Anile
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. V. Valentini
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to B. Diletto.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Balducci, M., Diletto, B., Chiesa, S. et al. Low-dose fractionated radiotherapy and concomitant chemotherapy for recurrent or progressive glioblastoma. Strahlenther Onkol 190, 370–376 (2014). https://doi.org/10.1007/s00066-013-0506-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00066-013-0506-z

Keywords

Schlüsselwörter

Search

Navigation